Toluene diisocyanate (TDI) is a highly reactive, volatile, low molecular weight compound used widely in the manufacture of polyurethane plastics. An estimated 50-100,000 persons in the U.S. have regular occupational exposure to isocyanates. Five to 10% of workers exposed to TDI develop an acute or chronic asthma syndrome. The pathogenesis of TDI-induced asthma is poorly understood. In both workplace and laboratory settings, exposure to TDI can lead to the development of asthma in subjects that have had prior cutaneous or inhalation exposure. This phenomenon suggests that TDI asthma results from immune sensitization and a subsequent immune response that elicits symptoms and altered pulmonary function. Extensive research has failed to show conclusive evidence for antibody-mediated hypersensitivity responses in the initiation or propagation of TDI asthma. This proposal examines a new hypothesis on the pathogenesis of asthma induced by TDI, which states that: 1) initial cutaneous and/or respiratory exposure, and subsequent airway challenge with TDI induces a T cell-dependent pulmonary delayed-type hypersensitivity inflammatory response, and 2) the inflammatory cells and mediators comprising TDI-induced pulmonary DTH play a critical role in the development of airway hyperreactivity. The experimental approach to test this hypothesis will be to: 1) establish optimal sensitization and challenge conditions for eliciting TDI-induced pulmonary DTH using a mouse model; 2) characterize and quantitate TDI-induced pulmonary DTH responses both immunologically and physiologically; and 3) examine antigen-specificity of TDI-induced pulmonary DTH. This research will lead to an improved understanding of the cellular events mediating TDI asthma, and also has potential implications for understanding the pathogenesis of inflammation seen in other forms of asthma. This work may ultimately lead to improved detection, prevention and treatment of TDI-induced airways disease.